Despite recent advances in lipid lowering therapy, atherosclerosis remains a leading cause of cardiovascular disease. SR-A, which is primarily expressed by macrophages, promotes both ligand internalization and cell adhesion. The ability of SR-A to mediate different macrophage functions suggests that it may have multiple roles in the pathogenesis of atherosclerosis. Understanding the role of SR-A in atherosclerosis requires the ability to independently study SR-A-mediated ligand internalization and macrophage adhesion. Therefore, identifying the structural features and cellular mechanisms that regulate SR- A function may help in understanding the role of this receptor in atherosclerosis. Our preliminary results indicate that SR-A-mediated cell adhesion and ligand internalization involve distinct cytoplasmic domains and activation of different intracellular signaling pathways. Moreover, our data suggest that the physiologic role of SR-A may depend, in part, upon the level of SR-A expression and the relative abundance of immobilized and soluble SR-A ligand. Thus, the hypothesis of this proposal is that SR-A binding to modified matrix proteins localizes SR-A with intracellular signaling proteins involved in macrophage adhesion and promotes macrophage accumulation in atherosclerotic plaques. The creation of receptor constructs that mediate cell adhesion but not ligand internalization or mediate ligand internalization but not cell adhesion provides us with unique reagents that allow us to test this hypothesis. Our first aim is to define the structural domains that couple SR-A to ligand internalization and cell adhesion. These studies will define the structural features required for SR-A-mediated cell adhesion and ligand internalization via endocytosis or phagocytosis. Our second aim is to determine the relationship between SR-A localization and function. Studies proposed in this aim will use biochemical and cell biological approaches to examine a previously undefined role for SR-A localization in lipid rafts in distinguishing SR-A-mediated functions. Our final aim is to determine the importance of SR-A-mediated ligand internalization and macrophage adhesion in atherogenesis. These studies take advantage of a bone marrow transfer approach to express unique SR-A constructs that mediate only cell adhesion or ligand internalization to determine the relative contribution of these functions in atherosclerosis. Overall, completion of the proposed studies will further our understanding regarding the role of SR-A in regulating macrophage function and atherogenesis. With this understanding, it may be possible to design therapeutic approaches that target specific macrophage functions to reduce atherosclerosis and enhance the benefit of lipid lowering. PUBLIC HEALTH RELEVANCE: Despite recent advances in lipid lowering therapy, atherosclerosis remains a leading cause of cardiovascular disease. Class A scavenger receptors (SR-A) are particularly interesting therapeutic targets as they mediate multiple activities that may differentially affect macrophage participation in the development of atherosclerosis. A better understanding of the role of SR-A in regulating specific macrophage functions may identify new therapeutic approaches that will reduce atherosclerosis and will enhance the benefit of lipid lowering.